Real-world pharmacogenetics of statin intolerance: effects of SLCO1B1, ABCG2, and CYP2C9 variants

Abstract

<div><div><div><h3>Objective </h3><p>The association of <em>SLCO1B1</em> c.521T>C with simvastatin-induced muscle toxicity is well characterized. However, different statins are subject to metabolism and transport also by other proteins exhibiting clinically meaningful genetic variation. Our aim was to investigate associations of <em>SLCO1B1</em> c.521T>C with intolerance to atorvastatin, fluvastatin, pravastatin, rosuvastatin, or simvastatin, those of <em>ABCG2</em> c.421C>A with intolerance to atorvastatin, fluvastatin, or rosuvastatin, and that of <em>CYP2C9*2</em> and <em>*3</em> alleles with intolerance to fluvastatin.</p><h3>Methods </h3><p>We studied the associations of these variants with statin intolerance in 2042 patients initiating statin therapy by combining genetic data from samples from the Helsinki Biobank to clinical chemistry and statin purchase data.</p><h3>Results </h3><p>We confirmed the association of <em>SLCO1B1</em> c.521C/C genotype with simvastatin intolerance both by using phenotype of switching initial statin to another as a marker of statin intolerance [hazard ratio (HR) 1.88, 95% confidence interval (CI) 1.08–3.25, <em>P</em> = 0.025] and statin switching along with creatine kinase measurement (HR 5.44, 95% CI 1.49–19.9, <em>P</em> = 0.011). No significant association was observed with atorvastatin and rosuvastatin. The sample sizes for fluvastatin and pravastatin were relatively small, but <em>SLCO1B1</em> c.521T>C carriers had an increased risk of pravastatin intolerance defined by statin switching when compared to homozygous reference T/T genotype (HR 2.11, 95% CI 1.01–4.39, <em>P</em> = 0.047).</p><h3>Conclusion </h3><p>The current results can inform pharmacogenetic statin prescribing guidelines and show feasibility for the methodology to be used in larger future studies.</p></div></div></div>